tbuckley/cabot-search huggingface dataset:
PB2580: THE VALUE OF HEMATOLOGIC INFLAMMATION INDICES FOR COVID–19 PATIENTS
Authors: Eleni Petridou, Effrosyni Evripioti, Athanasia Agorasti
Journal: HemaSphere (2023)

Topic: 30. Infections in hematology (incl. supportive care/therapy) Background: Coronavirus disease 2019 (COVID–19) patients are usually classified as “mild”, “severe” and “critical” types. The early identification of patients who need hospitalization upon admission in the Emergency Room is vital. The inflammation markers calculated from the data provided by the Complete Blood Count (CBC) are easily obtained at a low cost. Systemic Immune–Inflammation index (SII) & Neutrophil–to–Lymphocyte Ratio (NLR) are promising prognostic predictors for cancer patients. Aims: The aim of this study is to evaluate the predictive value of hematologic parameters such as the inflammation indices SII & NLR to exclude patients with COVID–19 who need to be treated as outpatients. Methods: Patients admitted to the Emergency Room of our hospital with COVID–19, diagnosed through real-time reverse transcription polymerase chain reaction, had a CBC on Sysmex XN-1000 automated hematology analyzer at the core Hematology Laboratory. We retrospectively recorded the demographic data and the laboratory findings upon admission: absolute neutrophil count (Neut, x109/L), absolute lymphocyte count (Lympho, x109/L) and platelet count (PLT, x109/L). We calculated the inflammation indexes as followed: SII = neut x PLT/ lympho & NLR = neut/ lympho. All study parameters were retrieved from the hospital electronic database system. Patients were divided into two groups: patients discharged and treated as outpatients (group A, N=100) and patients hospitalized in COVID–19 inpatient wards (group B, N=173). Statistical analysis: Data are referred as median and percentiles. The Mann-Whitney test, the Pearson Chi-Square test and the Receiver Operating Characteristic (ROC) curve with Area Under the Curve (AUC) were applied. P value of <0.05 was considered significant for all data analysis. Results: The two groups do not differ in gender (P=0.265) but inpatients are older [70 (58-79) vs 59 (39-70) years, P=0.009]. The two groups differ in a statistically significant degree in both indices; SII [A: 520.99 (295.70-1069.17) vs B: 841.37 (479.15-1460.12), P=0.025] and NLR [A: 2.69 (1.68-4.73) vs B: 4.44 (2.92-7.60), P=0.002]. The AUC in discriminating outpatients (consider as the positive actual state) is statistically significant for SII 0.637 (P=0.035) and for NLR 0.681 (P=0.034). The following cutoff values for SII >648.315 and NLR >3.42 exclude the possibility of discharging and treating as outpatient [Negative Predictive Value: 76.2% and 77.3%, respectively]. Pearson Chi-Square test for SII & NLR criteria revealed values 22.55 and 29.41, respectively, with both P <0.001. Summary/Conclusion: The hematologic inflammation indices SII & NLR, easily obtained with CBC analysis by calculation, are associated to the appropriate treatment a COVID–19 patient should receive. Keywords: Neutrophil, Inflammation, Platelet count, Lymphocyte
A phase III randomized crossover trial of plerixafor versus G-CSF for treatment of WHIM syndrome
Authors: David H. McDermott, Daniel Velez, Elena Cho, Edward W. Cowen, John J. DiGiovanna, Diana V. Pastrana, Christopher B. Buck, Katherine R. Calvo, Pamela J. Gardner, Sergio D. Rosenzweig, Pamela Stratton, Melissa A. Merideth, H. Jeffrey Kim, Carmen Brewer, James D. Katz, Douglas B. Kuhns, Harry L. Malech, Dean Follmann, Michael P. Fay, Philip M. Murphy
Journal: Journal of Clinical Investigation (2023)

BACKGROUNDWarts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a primary immunodeficiency disorder caused by heterozygous gain-of-function CXCR4 mutations. Myelokathexis is a kind of neutropenia caused by neutrophil retention in bone marrow and in WHIM syndrome is associated with lymphopenia and monocytopenia. The CXCR4 antagonist plerixafor mobilizes leukocytes to the blood; however, its safety and efficacy in WHIM syndrome are undefined.METHODSIn this investigator-initiated, single-center, quadruple-masked phase III crossover trial, we compared the total infection severity score (TISS) as the primary endpoint in an intent-to-treat manner in 19 patients with WHIM who each received 12 months treatment with plerixafor and 12 months treatment with granulocyte CSF (G-CSF, the standard of care for severe congenital neutropenia). The treatment order was randomized for each patient.RESULTSPlerixafor was nonsuperior to G-CSF for TISS (P = 0.54). In exploratory endpoints, plerixafor was noninferior to G-CSF for maintaining neutrophil counts of more than 500 cells/μL (P = 0.023) and was superior to G-CSF for maintaining lymphocyte counts above 1,000 cells/μL (P < 0.0001). Complete regression of a subset of large wart areas occurred on plerixafor in 5 of 7 patients with major wart burdens at baseline. Transient rash occurred on plerixafor, and bone pain was more common on G-CSF. There were no significant differences in drug preference or quality of life or the incidence of drug failure or serious adverse events.CONCLUSIONPlerixafor was not superior to G-CSF in patients with WHIM for TISS, the primary endpoint. Together with wart regression and hematologic improvement, the infection severity results support continued study of plerixafor as a potential treatment for WHIM syndrome.TRIAL REGISTRATIONClinicaltrials.gov NCT02231879.FUNDINGThis study was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases.
Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets
Authors: Jing Hua Zhao, David Stacey, Niclas Eriksson, Erin Macdonald-Dunlop, Åsa K. Hedman, Anette Kalnapenkis, Stefan Enroth, Domenico Cozzetto, Jonathan Digby-Bell, Jonathan Marten, Lasse Folkersen, Christian Herder, Lina Jonsson, Sarah E. Bergen, Christian Gieger, Elise J. Needham, Praveen Surendran, Andres Metspalu, Lili Milani, Reedik Mägi, Mari Nelis, Georgi Hudjašov, Dirk S. Paul, Ozren Polasek, Barbara Thorand, Harald Grallert, Michael Roden, Urmo Võsa, Tonu Esko, Caroline Hayward, Åsa Johansson, Ulf Gyllensten, Nick Powell, Oskar Hansson, Niklas Mattsson-Carlgren, Peter K. Joshi, John Danesh, Leonid Padyukov, Lars Klareskog, Mikael Landén, James F. Wilson, Agneta Siegbahn, Lars Wallentin, Anders Mälarstig, Adam S. Butterworth, James E. Peters
Journal: Nature Immunology (2023)

Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-α in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization.
Clinical-genomic determinants of immune checkpoint blockade response in head and neck squamous cell carcinoma
Authors: Cristina Valero, Mahdi Golkaram, Joris L. Vos, Bin Xu, Conall Fitzgerald, Mark Lee, Shannon Kaplan, Catherine Y. Han, Xin Pei, Reith Sarkar, Lillian A. Boe, Abhinav Pandey, Elizabeth S. Koh, Charlotte L. Zuur, David B. Solit, Traci Pawlowski, Li Liu, Alan L. Ho, Diego Chowell, Nadeem Riaz, Timothy A. Chan, Luc G.T. Morris
Journal: Journal of Clinical Investigation (2023)

BACKGROUND. Recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) is often an incurable disease, with patients experiencing median survival of under ten months and significant morbidity. While immune checkpoint blockade (ICB) drugs are effective in ~20% of patients, the remaining experience limited clinical benefit and are exposed to potential adverse effects and financial costs. Clinically approved biomarkers, such as tumor mutational burden (TMB), have modest predictive value in HNSCC.
Factors associated with healthy aging in Latin American populations
Authors: Hernando Santamaria-Garcia, Agustín Sainz-Ballesteros, Hernán Hernandez, Sebastian Moguilner, Marcelo Maito, Carolina Ochoa-Rosales, Michael Corley, Victor Valcour, J. Jaime Miranda, Brian Lawlor, Agustin Ibanez
Journal: Nature Medicine (2023)

Abstract Latin American populations may present patterns of sociodemographic, ethnic and cultural diversity that can defy current universal models of healthy aging. The potential combination of risk factors that influence aging across populations in Latin American and Caribbean (LAC) countries is unknown. Compared to other regions where classical factors such as age and sex drive healthy aging, higher disparity-related factors and between-country variability could influence healthy aging in LAC countries. We investigated the combined impact of social determinants of health (SDH), lifestyle factors, cardiometabolic factors, mental health symptoms and demographics (age, sex) on healthy aging (cognition and functional ability) across LAC countries with different levels of socioeconomic development using cross-sectional and longitudinal machine learning models ( n = 44,394 participants). Risk factors associated with social and health disparities, including SDH ( β &gt; 0.3), mental health ( β &gt; 0.6) and cardiometabolic risks ( β &gt; 0.22), significantly influenced healthy aging more than age and sex (with null or smaller effects: β &lt; 0.2). These heterogeneous patterns were more pronounced in low-income to middle-income LAC countries compared to high-income LAC countries (cross-sectional comparisons), and in an upper-income to middle-income LAC country, Costa Rica, compared to China, a non-upper-income to middle-income LAC country (longitudinal comparisons). These inequity-associated and region-specific patterns inform national risk assessments of healthy aging in LAC countries and regionally tailored public health interventions.
Nonviral base editing of KCNJ13 mutation preserves vision in a model of inherited retinal channelopathy
Authors: Meha Kabra, Pawan K. Shahi, Yuyuan Wang, Divya Sinha, Allison Spillane, Gregory A. Newby, Shivani Saxena, Yao Tong, Yu Chang, Amr A. Abdeen, Kimberly L. Edwards, Cole O. Theisen, David R. Liu, David M. Gamm, Shaoqin Gong, Krishanu Saha, Bikash R. Pattnaik
Journal: Journal of Clinical Investigation (2023)

Clinical genome editing is emerging for rare disease treatment, but one of the major limitations is the targeting of CRISPR editors delivery. We delivered base editors to the retinal pigmented epithelium (RPE) in the mouse eye using silica nanocapsules (SNC) as a treatment for retinal degeneration. Leber Congenital Amaurosis (LCA16) is a rare pediatric blindness caused by point mutations in the KCNJ13 gene, a loss-of-function inwardly rectifying potassium channel (Kir7.1) in the RPE. SNC carrying adenine base editor (ABE8e) mRNA and single-guide RNA precisely and efficiently corrected KCNJ13W53X/W53X mutation. Editing in both patient fibroblasts (47%) and human-induced pluripotent stem cell-derived RPE (LCA16-iPSC-RPE) (17%) had a negligible off-target response. We detected functional Kir7.1 channels in the edited LCA16-iPSC-RPE. In the LCA16 mouse model (Kcnj13W53X/+∆R), RPE cells targeted SNC delivery of ABE8e mRNA preserved normal visual function measured by full-field electroretinogram (ERG). Moreover, multifocal ERG confirmed the topographic measure of electrical activity primarily originating from the edited retinal area at the injection site. Preserved retina structure, post-treatment, was established by Optical Coherence Tomography (OCT). This preclinical validation of targeted ion channel functional rescue, a challenge for pharmacological and genomic interventions, reinforced the effectiveness of nonviral genome editing therapy for rare inherited disorders.
Mast cell activation in lungs during SARS-CoV-2 infection associated with lung pathology and severe COVID-19
Authors: Janessa Y.J. Tan, Danielle E. Anderson, Abhay P.S. Rathore, Aled O’Neill, Chinmay Kumar Mantri, Wilfried A.A. Saron, Cheryl Q.E. Lee, Chu Wern Cui, Adrian E.Z. Kang, Randy Foo, Shirin Kalimuddin, Jenny G. Low, Lena Ho, Paul Tambyah, Thomas W. Burke, Christopher W. Woods, Kuan Rong Chan, Jörn Karhausen, Ashley L. St. John
Journal: Journal of Clinical Investigation (2023)

Lung inflammation is a hallmark of Coronavirus disease 2019 (COVID-19) in patients who are severely ill, and the pathophysiology of disease is thought to be immune mediated. Mast cells (MCs) are polyfunctional immune cells present in the airways, where they respond to certain viruses and allergens and often promote inflammation. We observed widespread degranulation of MCs during acute and unresolved airway inflammation in SARS-CoV-2-infected mice and nonhuman primates. Using a mouse model of MC deficiency, MC-dependent interstitial pneumonitis, hemorrhaging, and edema in the lung were observed during SARS-CoV-2 infection. In humans, transcriptional changes in patients requiring oxygen supplementation also implicated cells with a MC phenotype in severe disease. MC activation in humans was confirmed through detection of MC-specific proteases, including chymase, the levels of which were significantly correlated with disease severity and with biomarkers of vascular dysregulation. These results support the involvement of MCs in lung tissue damage during SARS-CoV-2 infection in animal models and the association of MC activation with severe COVID-19 in humans, suggesting potential strategies for intervention.
Nucleus accumbens D1/D2 circuits control opioid withdrawal symptoms in mice
Authors: Yongsheng Zhu, Kejia Wang, Tengfei Ma, Yuanyuan Ji, Yin Lou, Xiaoyu Fu, Ye Lu, Yige Liu, Wei Dang, Qian Zhang, Fangyuan Yin, Kena Wang, Bing Yu, Hongbo Zhang, Jianghua Lai, Yunpeng Wang
Journal: Journal of Clinical Investigation (2023)

The nucleus accumbens (NAc) is the most promising target for drug use disorder treatment. Deep brain stimulation (DBS) of NAc is effective for drug use disorder treatment. However, the mechanisms by which DBS produces its therapeutic effects remain enigmatic. Here, we define a behavioral cutoff criterion to distinguish depressive-like behaviors and non-depressive-like behaviors in mice after morphine withdrawal. We identified a basolateral amygdala (BLA) to NAc D1 medium spiny neuron (MSN) pathway that controls depressive-like behaviors after morphine withdrawal. Furthermore, the paraventricular nucleus of thalamus (PVT) to NAc D2 MSN pathway controls naloxone-induced acute withdrawal symptoms. Optogenetically induced long-term potentiation with κ-opioid receptor (KOR) antagonism enhanced BLA to NAc D1 MSN signaling and also altered the excitation/inhibition balance of NAc D2 MSN signaling. We also verified that a new 50 Hz DBS protocol reversed morphine withdrawal-evoked abnormal plasticity in NAc. Importantly, this refined DBS treatment effectively alleviated naloxone-induced withdrawal symptoms and depressive-like behaviors and prevented stress-induced reinstatement. Taken together, the results demonstrated that input- and cell type-specific synaptic plasticity underlies morphine withdrawal, which may lead to novel targets for the treatment of opioid use disorder.
Coadministered pneumococcal conjugate vaccine decreases immune response to hepatitis A vaccine: a randomized controlled trial
Authors: Marianna Riekkinen, Sari H. Pakkanen, Veronik Hutse, Inge Roukaerts, Jukka Ollgren, Helena Käyhty, Christian Herzog, Lars Rombo, Anu Kantele
Journal: Clinical Microbiology and Infection (2023)

We explored the influence of coadministration on safety and immunogenicity of the most common travellers' vaccine hepatitis A (HepA) and the pneumococcal conjugate vaccine (PCV) increasingly used both at home and before travel.Volunteers aged ≥18 years (n = 305) were randomly assigned 1:1:1 into three groups receiving: 13-valent PCV (PCV13) + HepA, PCV13, or HepA. Anti-pneumococcal IgG concentrations, opsonophagocytic activity (OPA) titres, and total hepatitis A antibody (anti-HAV) concentrations were measured before and 28 ± 3 days after vaccination. Adverse events (AEs) were recorded over 4 weeks.After vaccination, the anti-HAV geometric mean concentration was significantly lower in the PCV13+HepA than the HepA group: 34.47 mIU/mL (95% CI: 26.42-44.97 mIU/mL) versus 72.94 mIU/mL (95% CI: 55.01-96.72 mIU/mL), p < 0.001. Anti-HAV ≥10 mIU/mL considered protective was reached by 71 of 85 (83.5%) in the PCV13+HepA group versus 76 of 79 (96.2%) in the HepA group, p 0.008. The increases in anti-pneumococcal IgG and OPA levels were comparable in the PCV13+HepA and PCV13 groups, apart from a bigger rise in the PCV13+HepA group for serotype 3 (one-way ANOVA: serotype 3 IgG p 0.010, OPA p 0.002). AEs proved more frequent among those receiving PCV13 than HepA, but simultaneous administration did not increase the rates: ≥one AE was reported by 45 of 56 (80.4%) PCV13, 43 of 54 (79.6%) PCV13+HepA, and 25 of 53 (47.2%) HepA recipients providing structured AE data.Coadministration of HepA and PCV13 did not cause safety concerns, nor did it impact the patients' response to PCV13, apart from serotype 3. However, coadministered PCV13 significantly impaired antibody responses to HepA.
Modeling idiopathic autism in forebrain organoids reveals an imbalance of excitatory cortical neuron subtypes during early neurogenesis
Authors: Alexandre Jourdon, Feinan Wu, Jessica Mariani, Davide Capauto, Scott Norton, Livia Tomasini, Anahita Amiri, Milovan Suvakov, Jeremy D. Schreiner, Yeongjun Jang, Arijit Panda, Cindy Khanh Nguyen, Elise M. Cummings, Gloria Han, Kelly Powell, Anna Szekely, James C. McPartland, Kevin Pelphrey, Katarzyna Chawarska, Pamela Ventola, Alexej Abyzov, Flora M. Vaccarino
Journal: Nature Neuroscience (2023)
Specific quinone reductase 2 inhibitors reduce metabolic burden and reverse Alzheimer’s disease phenotype in mice
Authors: Nathaniel L. Gould, Gila R. Scherer, Silvia Carvalho, Khriesto Shurrush, Haneen Kayyal, Efrat Edry, Alina Elkobi, Orit David, Maria Foqara, Darshit Thakar, Tommaso Pavesi, Vijendra Sharma, Matthew Walker, Matthew Maitland, Orly Dym, Shira Albeck, Yoav Peleg, Nicolas Germain, Ilana Babaev, Haleli Sharir, Maya Lalzar, Boris Shklyar, Neta Hazut, Mohammad Khamaisy, Maxime Lévesque, Gilles Lajoie, Massimo Avoli, Gabriel Amitai, Bruce Lefker, Chakrapani Subramanyam, Brian Shilton, Haim Barr, Kobi Rosenblum
Journal: Journal of Clinical Investigation (2023)

Biological aging can be described as accumulative, prolonged metabolic stress and is the major risk factor for cognitive decline and Alzheimer's disease (AD). Recently, we identified and described a quinone reductase 2 (QR2) pathway in the brain, in which QR2 acts as a removable memory constraint and metabolic buffer within neurons. QR2 becomes overexpressed with age, and it is possibly a novel contributing factor to age-related metabolic stress and cognitive deficit. We found that, in human cells, genetic removal of QR2 produced a shift in the proteome opposing that found in AD brains while simultaneously reducing oxidative stress. We therefore created highly specific QR2 inhibitors (QR2is) to enable evaluation of chronic QR2 inhibition as a means to reduce biological age-related metabolic stress and cognitive decline. QR2is replicated results obtained by genetic removal of QR2, while local QR2i microinjection improved hippocampal and cortical-dependent learning in rats and mice. Continuous consumption of QR2is in drinking water improved cognition and reduced pathology in the brains of AD-model mice (5xFAD), with a noticeable between-sex effect on treatment duration. These results demonstrate the importance of QR2 activity and pathway function in the healthy and neurodegenerative brain and what we believe to be the great therapeutic potential of QR2is as first-in-class drugs.
Novel insights into the pathogenesis of follicular lymphoma by molecular profiling of localized and systemic disease forms
Authors: Sabrina Kalmbach, Michael Grau, Myroslav Zapukhlyak, Ellen Leich, Vindi Jurinovic, Eva Hoster, Annette M. Staiger, Katrin S. Kurz, Oliver Weigert, Erik Gaitzsch, Verena Passerini, Marianne Engelhard, Klaus Herfarth, Klaus Beiske, Francesca Micci, Peter Möller, Heinz-Wolfram Bernd, Alfred C. Feller, Wolfram Klapper, Harald Stein, Martin-Leo Hansmann, Sylvia Hartmann, Martin Dreyling, Harald Holte, Georg Lenz, Andreas Rosenwald, German Ott, Heike Horn
Journal: Leukemia (2023)

Knowledge on the pathogenesis of FL is mainly based on data derived from advanced/systemic stages of FL (sFL) and only small cohorts of localized FL (lFL) have been characterized intensively so far. Comprehensive analysis with profiling of somatic copy number alterations (SCNA) and whole exome sequencing (WES) was performed in 147 lFL and 122 sFL. Putative targets were analyzed for gene and protein expression. Overall, lFL and sFL, as well as BCL2 translocation-positive (BCL2+) and -negative (BCL2-) FL showed overlapping features in SCNA and mutational profiles. Significant differences between lFL and sFL, however, were detected for SCNA frequencies, e.g., in 18q-gains (14% lFL vs. 36% sFL; p = 0.0003). Although rare in lFL, gains in 18q21 were associated with inferior progression-free survival (PFS). The mutational landscape of lFL and sFL included typical genetic lesions. However, ARID1A mutations were significantly more often detected in sFL (29%) compared to lFL (6%, p = 0.0001). In BCL2 + FL mutations in KMT2D, BCL2, ABL2, IGLL5 and ARID1A were enriched, while STAT6 mutations more frequently occurred in BCL2- FL. Although the landscape of lFL and sFL showed overlapping features, molecular profiling revealed novel insights and identified gains in 18q21 as prognostic marker in lFL.
No evidence that Chinese playtime mandates reduced heavy gaming in one segment of the video games industry
Authors: David Zendle, Catherine Flick, Elena Gordon-Petrovskaya, Nick Ballou, Leon Y. Xiao, Anders Drachen
Journal: Nature Human Behaviour (2023)

Abstract Governments around the world are considering regulatory measures to reduce young people’s time spent on digital devices, particularly video games. This raises the question of whether proposed regulatory measures would be effective. Since the early 2000s, the Chinese government has been enacting regulations to directly restrict young people’s playtime. In November 2019, it limited players aged under 18 to 1.5 hours of daily playtime and 3 hours on public holidays. Using telemetry data on over seven billion hours of playtime provided by a stakeholder from the video games industry, we found no credible evidence for overall reduction in the prevalence of heavy playtime following the implementation of regulations: individual accounts became 1.14 times more likely to play heavily in any given week (95% confidence interval 1.139–1.141). This falls below our preregistered smallest effect size of interest (2.0) and thus is not interpreted as a practically meaningful increase. Results remain robust across a variety of sensitivity analyses, including an analysis of more recent (2021) adjustments to playtime regulation. This casts doubt on the effectiveness of such state-controlled playtime mandates.
Impact of Concurrent Genomic Alterations on Clinical Outcomes in Patients With ALK-Rearranged NSCLC
Authors: Luis Lara-Mejía, Andres F. Cardona, Luis Mas, Claudio Martin, Suraj Samtani, Luis Corrales, Graciela Cruz-Rico, Jordi Remon, Marco Galvez-Nino, Rossana Ruiz, Eduardo Rios-Garcia, Fernanda Tejada, Natalia Lozano-Vazquez, Rafael Rosell, Oscar Arrieta
Journal: Journal of Thoracic Oncology (2023)